Process

ABSTRACT

The present invention relates to a process using ultrasonic cutting for the preparation of an oral delivery device comprising a core which includes a pharmaceutically active agent covered by an outer coating which includes one or more openings communicating from the exterior of the device toward the core.

The present invention relates to a novel process for the preparation ofan oral delivery device for a pharmaceutically active agent. Inparticular, the invention relates to a process for the preparation of anoral delivery device comprising a core which contains the active agent,having a coating with one or more openings leading toward such a core.

There is a requirement in the art to prepare oral delivery devicescomprising a core which contains a pharmaceutically active agent, andhaving a coating with one or more openings leading to such a core. Inparticular, there is requirement to prepare such devices that can beused to deliver a drug substance, at a controlled rate of release, to anenvironment of use. Some of the devices utilised for this purpose arediscussed in U.S. Pat. No. 5,004,614, which particularly relates to acontrolled release device with an impermeable coating having an orificefor release of drug when the device has been orally administered and isimmersed in an aqueous medium such as gastro-intestinal fluid. Theimpermeable coating of such a device may be applied to a tablet coreaccording to standard pharmaceutical formulations (e.g. dip coating,compression coating etc.) and the orifice formed by removing sections ofthe formed coating by laser or mechanical drilling.

It has now been found that one or more openings of various size andshape may be formed in an oral delivery device more rapidly andaccurately than that provided by known drilling techniques. Thus, it isan object of this invention to provide an alternative process for thepreparation of oral delivery devices having a coating with one or moreopenings leading to a tablet core. It is a particular object of thisinvention to provide an improved process for the manufacture of devicesof the type disclosed in U.S. Pat. No. 5,004,614, the contents of whichare incorporated herein by reference. It is also an object of theinvention to provide novel constructions of devices of this generaltype. Other objects and advantages of the invention will become apparentfrom the following description.

The present invention therefore provides, in a first aspect, a processfor the preparation of an oral delivery device comprising a core whichincludes a pharmaceutically active agent, the core covered by an outercoating which includes one or more openings communicating from theexterior of the device toward the core characterised in that the saidone or more openings is/are formed by removal of one or more sections ofsaid outer coating by application of vibrational energy of ultrasonicfrequency to the outer coating.

A process for making a device according to this invention may, forexample, form part of a larger process which comprises the steps of:

-   -   preparing the core of the device comprising a pharmaceutically        active agent;    -   coating the core of the device with an outer coating to thereby        form a coated device;    -   situating the coated device in a position adapted to receive a        horn by means of which ultrasonic energy may be transmitted to a        location adjacent to the horn;    -   applying the horn at one or more locations of the coated device        to thereby disrupt the outer coating;    -   removing disrupted outer coating material to thereby provide a        coated device with one or more openings in the outer coating        communicating from the exterior toward the core of the device.

The core of the device may be prepared by compressing suitableingredients for the core, e.g. powder or granulates to form a compactedmass which comprise the core of the device (also referred to herein as“tablet core”). This may be prepared using conventional tabletexcipients and formulation compression methods. Thus, the core wouldtypically comprise the active agent or agents along with excipients thatimpart satisfactory processing and compression characteristics such asdiluents, binders and lubricants. Additional excipients that may formpart of the core of the device include flavourants, colorants andrelease modifying agents. Typically the active agent and excipients arethoroughly mixed prior to compression into a solid core. The core of thedevice can be formed by, for example, wet granulation methods, drygranulation methods, direct compression or by melt extrusion. The corecan be produced according to any desired pre-selected shape such asbi-convex, hemi-spherical, near hemi-spherical, round, oval, generallyellipsoidal, oblong, generally cylindrical or polyhedral, e.g. atriangular prism shape. The term “near hemispherical” is intended to beconstrued in the manner described in U.S. Pat. No. 5,004,614. Preferablythe core is formulated into a bi-convex shape, e.g. having two domedopposite surfaces. In addition, the core could be produced in amulti-layered (e.g. bi- or tri-layered) form. The core can compriseactive agents which are suitable for use in a wide range of therapiesand include those listed in U.S. Pat. No. 5,004,614. The quantity ofactive agent present within the core is a matter to be determined basedupon typical pharmaceutical considerations, e.g. known dosages for theactive materials contained therein, and is not limited by the process ofthis invention.

The compacted mass which comprises the core is then coated with asuitable outer coating material which can be applied to the core byconventional procedures. For example, the coating may be formed by filmformation from a polymer in solution or suspension by pouring orspraying onto a pre-formed core. Alternatively, a core may be dipcoated, melt coated or coated using known injection moulding processes.The thickness of the outer coating may for example be in the range of1-2000 microns, although a coating thickness in the range 10 to 500microns would typically be preferred. Alternatively, as is common in thepharmaceutical industry the amount of coating can be expressed in termsof the relative weight of coating material applied to the core.Generally as a rule of thumb, for cores of a size suitable for an oralpharmaceutical tablet every 1% of coating corresponds to ca. 10 micronsthickness of coat. Typically on such a basis, the weight of coating mayamount to about 1-20% of the total weight of the core and outer coating.

The outer coating may comprise a water soluble coating which may forexample be an aqueous film coating. Such coating materials are wellknown in the art. Particularly preferred examples of such materialsinclude hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose(HPMC) and the like.

Preferably the outer coating is “impermeable”, that is to say, a coatingthat has properties that delay, obstruct or prevent influx ofenvironmental fluids, e.g. a gastro-intestinal fluid, during apre-determined time. Thus, such an outer coating can block exposure ofthe core to such fluids and preferably is not removed by dissolution orotherwise disrupted, before a pre-determined duration has passed. Forexample such a coating may be preferentially dissolve or rupture at thepH of a determined part of the gastro-intestinal system such as theintestine, so release of the active agent in significant quantity doesnot occur until the coated device reaches that part. The term“impermeable” is also intended to include a coating material that,whilst being to some degree permeable to environmental fluids, iscapable of preventing exposure of the core except through the one ormore openings sufficiently long to allow a pre-determined quantity ofdrug to be released. It will be appreciated by those skilled in the artthat where the outer coating material used does exhibit a certain degreeof permeability to environmental fluids, a thicker coating may benecessary to achieve the desired degree of impermeability. The outercoating may be comprised of any acceptable material, or blends thereof,which provide or can be adapted to provide an impermeable coating.Representative examples of such materials include those listed in U.S.Pat. No. 5,004,614.

Particularly preferred examples of materials suitable for such coatingsinclude ethylcellulose (e.g. those sold under the trade nameSurelease™), polymethacrylate copolymers (e.g. those sold under thetrade name Eudragit™ and Acrylease™), and polyvinyl acetate phthalatematerials (e.g. as sold under the trade name Sureteric™), biodegradablematerials and hydrophobic polymers in general. The process of theinvention has been found suitable to provide openings in coatingscomprised of such materials.

The outer coating may comprise a single layer, or for example it may bea multi-layer coating, for example discrete respective layers comprisedof the above-mentioned materials. A multi-layer outer coating maycomprise an adhesive layer, for example comprised of shellac orpolyvinyl acetate phthalate to facilitate the sticking of a layer toanother underlying or overlying layer, or to the core prior toapplication of an outer layer. Alternatively a multi-layer outer coatingmay comprise a releasing layer which is relatively non-adhering to anadjacent layer, particularly an outwardly adjacent coating, tofacilitate the removal of the material of the adjacent layer when thisis disrupted by the process of the invention. A multi-layer outercoating may comprise a layer which has a desirable texture orappearance, overlying an underlying layer or the core itself, with aless attractive texture or appearance. For example the core, typicallybeing made by compression of granules, may have a rough surface,considered less attractive by some, and a layer may be used in this way.A multi-layer outer coating may for example comprise a sealing layerwhich protects the core prior to use, typically being soluble ingastro-intestinal fluids. Hydroxypropylmethyl cellulose (“HPMC”) is amaterial suitable as a sealing layer and/or as a layer with anattractive smooth surface over the surface of the core.

Such layers of a multi-layer outer coating will normally be very thin,but it has been found that the process of the invention, usingultrasonic disruption of the coating material, enables extreme precisionin the depth of outer coating material disrupted and removed, therebyallowing selective removal of all or part of the thickness of one ormore layer.

The opening(s) in the coating of the device is/are formed by removal ofone or more sections of outer coating. For the avoidance of doubt, theterm “opening” is to be taken as being synonymous with orifice, hole,passageway, aperture etc.

The one or more opening may pass all the way through the coating, i.e.providing open communication from the exterior environment of the deviceto the core, and in such a case the outer coating is disrupted to adepth sufficient to communicate with the core of the device. In such amode of operation of the process of the invention the horn may disruptonly the outer coating material (whether single or multi-layer) withoutdisrupting the core, or alternatively the horn may also disrupt corematerial so that the opening penetrates into the core.

Alternatively a thin layer of the coating material may be left over thecore at the bottom of the opening, i.e. by means of the horn disruptingonly outer coating material but not entirely penetrating the outercoating. If the coating material left over the core at the bottom of theopening is not entirely impermeable the thickness of such residualmaterial may be such that environmental fluids slowly penetrate thelayer and the active material content of the core slowly leaches out,and so maybe used to control the rate of release of the active material.For example if the outer coating is a multi-layer coat, then all or partof the thickness of one or some of the layers may be left as a residueof the coating material left over the core at the bottom of the opening,for example as an adhesive layer, a releasing layer, a layer of adesirable texture or appearance, or a sealing layer as described above.

Use of the process of this invention may result in an exposed tabletcore wherein some minor level of disruption of the tablet core surfacehas occurred. For aesthetic or any other purposes it may be desirable toapply an additional aqueous film coat around the coated device withopenings formed therein as a final stage in a larger process such asthat described above.

In a form of the process of the invention in which the outer coating ismulti-layer, a more consistent smooth tablet core structure that issuitable for use in a controlled release formulation, may be obtainedusing a process according to this invention which comprises the stepsof:

-   -   preparing the core of the device comprising a pharmaceutically        active agent;    -   coating the core of the device with a layer of a water soluble        coating, preferably an aqueous film coating;    -   coating the coated core with an impermeable outer coating to        thereby form a coated device;    -   situating the coated device in a position adapted to receive a        horn by means of which ultrasonic energy may be transmitted to a        location adjacent to the horn;    -   applying the horn at one or more locations of the coated device        to thereby disrupt the impermeable outer coating to a depth        sufficient to communicate with the water soluble coating;    -   removing disrupted impermeable outer coating material to thereby        provide a coated device with one or more openings which are        closed by a temporary protective cover provided by the water        soluble coating situated between the core and the exterior of        the device.

Certain devices as described above appear to be novel, therefore in afurther aspect the invention provides an oral delivery device comprisinga core which includes a pharmaceutically active agent, the core coveredby an outer coating which includes one or more openings in the outercoating communicating from the exterior of the device toward the core,with a thin layer of the coating material over the core at the bottom ofthe opening. In an embodiment of this device the outer coating ismulti-layer comprising plural layers, and all or part of the thicknessof one or some of the layers is present over the core at the bottom ofthe opening.

Initially, i.e. prior to administration to a patient, the one or moreopenings may also initially be closed by a temporary protective coversituated between the core and the exterior of the device. Such atemporary cover may be prepared from a water soluble material thatreadily dissolves in gastrointestinal fluids, and thereby fully exposingthe core to the exterior of the device.

The number, relative position, shape and size of openings formed in theouter coating may be chosen, inter alia, to effect the desired releaserate of active drug substance. The use of the process of this inventionplaces no limitation on these parameters. Thus, the process of thisinvention can be used to produce one or more openings at any position onthe device including any edges or faces that may be present. Suitably inthe depth direction the openings may have substantially parallel sides.Any single opening can be as small as 0.2 mm across and up to as largeas a face of the tablet core, e.g. 15 mm across although openings in therange 0.5 mm-6 mm across would be more typical. The openings may haveany convenient shapes, but are preferably rounded e.g. circular orelliptical. The openings can be arrayed in such a way and their number,relative position, shape and size may be so as to produce a design,trademark or other symbol such as a logo or a number e.g. identifyingthe quantity of active material etc. It follows from this that theprocess of this invention can be used to create a commercial image onthe surface of coated tablet dosage forms which are to be utilised forimmediate or controlled release.

The opening(s) of the device are formed by disrupting and removingsection(s) of outer coating by application of vibrational energy ofultrasonic frequency using an ultrasonic system. Disruption may involvethe outer coating material being destroyed, e.g. pulverised to fineparticles, or the outer coating material being removed substantiallyintact, for example when a circular opening is made the coating materialmay be removed as a small disc. The coating material may be removed inany disrupted form between these extremes.

The basic elements of an ultrasonic system and known uses thereof aredescribed by Rawson F. F. in “An introduction to ultrasonic foodcutting” (Ultrasound in Food Processing, Povey M. J. W and Mason T. J.(eds), Chapter 14, Thompson science, 1997, London, pages 255-269) and“Ultrasonic Technology in Today's Industry” (Physics Bulletin, Vol. 38,1987, pages 255-257), the contents of these references are incorporatedherein by reference. A key component of such a system is the shaped hornwhich is attached through a shaft to an ultrasonic source and whichdetermines the vibrational amplitude of the tip which is in contact withthe material being acted upon. The ultrasonic horn utilises a halfwavelength resonance section at for example 10-100 KHz, preferably 10-60KHz; more preferably 18-55 KHz, optimally around 40 KHz, with variableamplitude, and it should be mounted in a solid frame so that verticalmovement is possible upwards and downwards. Construction of such hornsand associated power and control equipment is well understood in theart, and suitable equipment is commercially available, e.g. via. RainbowEngineering Services, Letchworth, GB.

Suitably to form the opening the horn may have a tip which is applied tothe core and which is in the form of a sharp edge defining the perimeterof the opening. For example, to form a round opening such an edge may beof ring or annular shape.

Ultrasonic energy may be transmitted to the tip of the horn eitherbefore or after it is brought into contact with the outer coating.Preferably, the ultrasonic energy is switched on prior to the contactbeing made with the outer coating.

The cutting action is provided by a combination of the pressure appliedto the sharp edge cutting surface and the mechanical longitudinalvibration of the tip. The amplitude of longitudinal vibration is ofparticular importance and typically will be in the range 50-100 micronspeak to peak. The operating power is set in order to maintain therequisite amplitude. It will be appreciated by those skilled in the artof ultrasonic cutting that a different working tip amplitude might berequired to cut through an outer coating material when compared to thatrequired to cut through an outer coating material plus tablet corematerial. Ultrasonic cutting devices that are known in the art can bereadily programmed to provide the requisite working amplitudes. Itfollows from this that it is a matter of routine experimentation todetermine the optimum amplitude necessary to disrupt the outer coatingto a depth sufficient to communicate with the core of the device or anyother desired depth as outlined above.

The coated device is situated in a position adapted to the applicationof a horn of an ultrasonic system to the coating, and the device andhorn are relatively moved to apply the horn to the device. For theavoidance of doubt, this is intended to mean either that the coateddevice is moved relative to the ultrasonic system or alternatively, thatthe ultrasonic system is moved relative to the coated device. The latterarrangement may be employed, for instance, using a single device with ahand held ultrasonic system. Preferably, the coated device ismoved-relative to the ultrasonic system by any conventional ornon-conventional means. Suitable examples may include manual incursionand removal although an automated system would typically be employed.

For example one, or preferably plural coated devices may be retained ina holder, e.g. a dimple of corresponding shape in a plate, and the hornmay be applied downwardly to the device. The plate may be moved by asuitable X-Y translation engine to move successive coated devices into aposition suitable for the horn to be applied to each of the successivedevices.

The coated devices may be rotated, inverted or otherwise manoeuvred toallow for the production of openings on all sides of the coated device.It would be appreciated that openings in the outer coating of more thanone device could be made concurrently using, for example, a plurality ofcoated devices situated in a X-Y table and a plurality of hornsoperating in co-operation.

Preferably, the horn is also fitted with means to remove any disruptedouter coating material as the opening communicating from the exteriortoward the core of the device is made, and such means may be a vacuumline. For example, in the case of the above mentioned ring-shaped edgethe vacuum line may communicate with the interior of the ring. Forexample the horn may comprise a tubular part with the ring-shaped edgebeing at the open end of the tube, and the bore of the tube may beconnected to the vacuum line. A preferred form of the ring shaped edgeis provided by an end of the tubular part which is externallycylindrical, with the end of the bore immediately adjacent to the openend tapering conically internally to narrow away from the open end. Asuitable angle of taper is ca. 5-10°, e.g. ca. 7°. Conveniently such atubular part may have a side conduit leading from the bore to the outersurface of the tubular part, and the bore may be connected to the vacuumline via this side conduit. The connection may be achieved by means of asleeve with an internal bore fitting around the tubular part and havinga conduit passing through the wall of the sleeve to the exterior of thesleeve, and being connectable to the vacuum line. Suitably, seals suchas elastomer washers may be provided between the outer surface of thetubular part and the inner surface of the bore of the sleeve.

Such a construction facilitates the connection of the tubular part tothe vacuum line whilst applying ultrasonic energy to the horn. Thisconstruction of horn is believed to be novel.

It has been found, using the process of this invention, that one or moreopenings of varying size and shape may be rapidly and accurately formedin an oral delivery device. The primary advantage of the process of thisinvention over known laser drilling techniques is their relative speeds.This is particularly the case when a large opening (e.g. greater than 2mm across) is required in the outer coating. It has been found that anopening of such a magnitude can be formed using the process of thisinvention in less than 0.2 seconds. It follows from this that theprocess of this invention is therefore suitable for the large scalemanufacture of a pharmaceutical in which an output of 100,000 units perhour is often desirable. In addition, the low cutting forces employedwith an ultrasonic system gives rise to a lower level of disruption oftablet core. This in turn leads to a smaller product wastage (weightloss) particularly in comparison to known mechanical drillingtechniques. Such a process is therefore, highly cost effective withrelatively low running costs.

The invention will now be described by way of example only withreference to the accompanying drawings in which:

FIG. 1 shows a suitable horn for making a device of this invention, inlongitudinal and cross sections;

FIG. 2 shows a fully coated core comprising a pharmaceutically activedrug substance and excipients;

FIGS. 3, 4 and 5 show devices prepared in accordance with thisinvention.

Referring to FIG. 1, the horn 20 is made of titanium, and comprises agenerally cylindrical shaped tubular part narrowing to a tip 21 at adistal end. The tip 21 is ring-shaped in cross section, corresponding inshape to the cross section of the member 20, and is profiled into asharp edge 22 (machined as sharp as possible) having parallel, i.e.,cylindrical, outer sides. Longitudinally along the center of the horn 20is a bore 23, which may be connected to a vacuum line (not shown).Adjacent its open end 24, the bore tapers conically at a conical angleof ca. 7°, this profile being found suitable for effective cutting ofthe opening. Further downstream from the end 24, the internal borewidens internally, and from this wider part a side conduit 25 extendslaterally. Around the tubular part, adjacent the side conduit 25, is asleeve 26, with a bore closely conforming to the outer profile of thetubular part 20, and having a bore 27, which serves as a sleeve conduit,extending through its wall and leading to a vacuum connection 28.Between sleeve 26 and tubular part 20 are elastomeric ring washer seals29 located respectively proximally and distally from side conduit 25 andfrom bore 27. At its proximal end 210, opposite the tip 21, the horn 20is connected by a standard coupling 30 to a known ultrasonic generator31 for applying ultrasonic energy to the horn 20. The ultrasonicgenerator utilized was a Rainbow Ducane DEC Press System.

Referring to FIG. 2, a device is shown 10 overall comprising acompressed core 11 that is suitable for use in a controlled releaseformulation, and which consists of 10% of a pharmaceutically activeingredient, 40% hydroxypropylmethyl cellulose (HPMC), 29% lactose, 20%microcrystalline cellulose and 1% magnesium stearate. The core 11 ismade by mixing together the listed ingredients and compressing using aconventional powder compression process. The core 11 is entirelysurrounded by a coating 12 which is 10% (of total weight of core andcoating) of ethylcellulose, applied using a typical tablet coatingprocess. As coated, the tablet is of a bi-convex shape having upper andlower domed sides and a circular horizontal section cut perpendicular tothe plane of the drawing. The device is approximately 10 mm diameter inits circular cross section and about 4 mm thick, and the coating layeris approximately 150 microns thick.

In use the device 10 is securely supported, and the tip 21 of the hornis applied to the coating at a point 13 at the centre of one of thedomed surfaces. Ultrasonic energy is then transmitted to the horn andthen the tip 21 is pressed gently against the coating 12. The hornutilises a half wavelength resonance section at 18-55 KHz, preferablyca. 40 KHz, and is set to have an amplitude in the longitudinaldirection of 60 microns peak to peak, maintained by the operating powerof 50-100 W. Amplitude is measured as a percentage, a transducer in thesystem converting electrical energy to mechanical energy, to an outputof 10 micron. The mechanical energy is then transferred to the boosterof a particular ratio (e.g. 3:1) which increases the mechanical energy,this energy is finally transferred to the horn which again increases themechanical energy. The amplitude is the percent of this mechanicalenergy and in the art is a common way of expressing the set up of thesystem. Such operating conditions are easily within the normal operatingparameters of the system.

-   -   set by the operating power of 50-100 W. Such operating        conditions are easily within the normal operating parameters of        the system.

Referring to FIG. 3, the tip 21 has cut an opening 14 completely throughthe coating 12 so that the core 11 is exposed to the outside environmentof the device via the single opening. The opening 14 is substantiallycylindrical in profile. During the cutting operation the particles ofcoating 12 material which have been removed to form the opening 14 aresucked away via the bore 23, through the side conduit 25 and out throughconduit 27 of sleeve 26. It is advisable to incorporate an in-linefilter between the vacuum connection 28 and the vacuum line. Thediameter of the opening 14 is approximately 5.5 mm and was produced in acutting time of less than 0.1 seconds. The weight loss of core materialwas found to be approximately 2%.

In further experiments, cores identical to that described above werecoated with 15% of coatings being respectively a Eudragit™, a Surelease™material and a Suretic™ material, all available from Colorcon Ltd. (GB).Circular openings of diameters 5.0, 5.5 and 6.0 mm, with depths cutaccurately to predetermined distances ranging from 0.25-0.6 mm, were cutin the manner described above, using the same system at energy levelsranging from 2.8-10.0 J, peak power ranging from 50-105 W, and operatingamplitudes (an operating setting of the system) of 70-100%. Theseopenings took 0.06-0.15 seconds to cut. Further experiments successfullyaccurately cut openings 2.5 mm diameter.

Alternative forms of the device are shown in FIGS. 4 and 5.

Referring to FIG. 4, the tip 21 has cut an opening 15 partly through thecoating 12 so that the core 11 is covered by a thin layer 16 of thecoating material 12 at the bottom of the opening 15, so that the core isprotected from the outside environment of the device via the layer 16.The opening 15 is again substantially cylindrical in profile. It isfound that such accuracy of depth cutting can be achieved with the abovementioned system.

Referring to FIG. 5, a device 10 with an outer coating which ismulti-layer is shown. The outer coating layer comprises an inner layer17 of HPMC, and an outer layer 18 of Eudragit™ material. The amount ofeach of the layer 17, 18 materials was ca. 10% each. The tip 21 has cutan opening 19 completely through the outer layer 18, but not through theinner layer 17, which remains wholly or partly intact at the bottom ofthe opening 19, so that the core 11 remains covered by layer 17 at thebottom of the opening 19. The core 11 is made from granulated materialsso that it has a rough surface texture, and the HPMC layer 18 is of asmooth, attractive appearance. The inner layer 17 is exposed to theoutside environment of the device via the single opening. The opening 19is substantially cylindrical in profile. It is found that such accuracyof depth cutting can be achieved with the above-mentioned system.

It will be appreciated that the above examples are given by way ofillustration rather than limitation of the utility of this invention.

1. A process for the preparation of an oral delivery device comprising acore which includes a pharmaceutically active agent, the core covered byan outer coating which includes one or more openings extending from theexterior of the device toward the core, characterised in that the saidone or more openings is/are formed by removal of one or more sections ofsaid outer coating by application of vibrational energy of ultrasonicfrequency to the outer coating, wherein the vibrational energy isapplied to the outer coating by bringing into contact with the coating asharp, ring-shaped cutting edge of the tip of an ultrasonic hornextending longitudinally toward the coating and causing the horn tovibrate longitudinally at an ultrasonic frequency, whereby the sharpring-shaped cutting edge defines the perimeter of each said opening inthe outer coating, in which said horn has proximal and distal ends andcomprises a tubular part having a wall with a bore and an outer surface,and said bore has an open end at the distal end of the horn, with thesharp, ring-shaped cutting edge being at said open end, and the bore ofthe tubular part is connectable to a vacuum line, and wherein the stepof removing one or more sections of outer coating material is carriedout by drawing a vacuum through the bore of the tubular part, in which aportion of the tubular part adjacent said open end and extendingtherefrom is externally cylindrical, and an end portion of the boreextending from said open end has a conical taper that is narrower awayfrom the open end than at the open end, in which said tubular part has aside conduit leading laterally through said wall from the bore of thetubular part to the exterior of the tubular part, the bore isconnectable to a vacuum line via the side conduit by means of a sleevewith an internal bore having an inner surface fitting around the tubularpart and being sealed thereto by elastomeric ring seals provided betweenthe outer surface of the tubular part and the inner surface of the boreof the sleeve, said sleeve has a sleeve conduit passing through the wallof the sleeve to an outer surface of the sleeve, and the sleeve conduitis connectable at said outer surface to a vacuum line, said elastomericring seals are provided respectively on proximal and distal sides of thesleeve conduit and also located respectively on proximal and distalsides of the side conduit, whereby a vacuum connection is made betweensaid vacuum line and the bore of the tubular part, and in which the stepof drawing a vacuum is carried out by drawing a vacuum through said sideconduit and said sleeve conduit.
 2. A process for the preparation of anoral delivery device comprising a core which includes a pharmaceuticallyactive agent, the core covered by an outer coating which includes one ormore openings extending from the exterior of the device toward the core,characterised in that the said one or more openings is/are formed byremoval of one or more sections of said outer coating by application ofvibrational energy of ultrasonic frequency to the outer coating, whereinthe vibrational energy is applied to the outer coating by bringing intocontact with the coating a sharp, ring-shaped cutting edge of the tip ofan ultrasonic horn extending longitudinally toward the coating, andcausing the horn to vibrate longitudinally at an ultrasonic frequency,whereby the sharp ring-shaped cutting edge defines the perimeter of eachsaid opening in the outer coating, in which said horn has proximal anddistal ends and comprises a tubular part having a wall with a bore andan outer surface, and said bore has an open end at the distal end of thehorn, with the sharp, ring-shaped cutting edge being at said open end,and the bore of the tubular part is connectable to a vacuum line, andwherein the step of removing one or more sections of outer coatingmaterial is carried out by drawing a vacuum through the bore of thetubular part, and in which said tubular part has a side conduit leadinglaterally through said wall from the bore of the tubular part to theexterior of the tubular part, the bore is connectable to a vacuum linevia the side conduit by means of a sleeve with an internal bore havingan inner surface fitting around the tubular part and being sealedthereto by elastomeric ring seals provided between the outer surface ofthe tubular part and the inner surface of the bore of the sleeve, saidsleeve has a sleeve conduit passing through the wall of the sleeve to anouter surface of the sleeve, and the sleeve conduit is connectable atsaid outer surface to a vacuum line, said elastomeric ring seals areprovided respectively on proximal and distal sides of the sleeve conduitand also located respectively on proximal and distal sides of the sideconduit, whereby a vacuum connection is made between said vacuum lineand the bore of the tubular part, and in which the step of drawing avacuum is carried out by drawing a vacuum through said side conduit andsaid sleeve conduit.
 3. A process according to claim 2, in which thehorn is caused to vibrate longitudinally by application of ultrasonicenergy to the proximal end of the horn by means of an ultrasonicgenerator.
 4. A process according to claim 1, in which the horn iscaused to vibrate longitudinally by application of ultrasonic energy tothe proximal end of the horn by means of an ultrasonic generator.